Pilot: High-Grade Glioma and Their Treatments Induce Cognitive Impairment Via RedoxEVs

High-grade glioma (HGG) is the most common primary brain cancer in adults. Glioma patients endure not only cancer but also a decline in cognitive function before and after cancer therapy, which severely impacts daily quality of life. While the problem of cognitive impairment (CI) is well recognized, our understanding of the underlying mechanism is far from complete. The underlying pathogenesis of CI is complex, and a growing body of evidence implicates pathological protein aggregates as mechanisms commonly involved in many of the hallmark features of cognition lossrelated neurodegenerative diseases. HGG has a high level of reactive oxygen species (ROS), which generate the highly toxic lipid peroxidation product, 4-hydroxynonenal (HNE), leading to the inactivation of protein functions and to the accumulation of HNE-adducted protein aggregates. Our prior studies indicate that a primary ROS removal enzyme, manganese-containing superoxide dismutase (MnSOD), exhibits redox-active antioxidant (RAA) properties in protecting normal cells against ROS-mediated injury while enhancing radiation therapy of cancer cells. Our findings are consistent with recent reports showing that MnSOD mimetics exhibit RAA properties, serving as antioxidants in normal cells and prooxidants in cancer cells. In preliminary studies to elucidate the mechanistic underpinnings of CI in HGG, we found that MnSOD is adducted by HNE and accumulates in extracellular vesicles (RedoxEVs) released from the HGG cells and present in the serum of HGG patients that can cause the death of brain cells. We hypothesize that modulation of RedoxEV associated cytokines- and/or RedoxEVs-dependent prooxidant microenvironments in the brain with RAA, will reduce CI without reducing the efficacy of cancer therapeutics. We will test these novel hypotheses with two interrelated specific aims. Aim 1 will elucidate the mechanism and metabolism by which RedoxEVs induce neuronal injury via activation of glial cells. This aim will define the RedoxEVs-dependent ROS and Redox-dependent metabolism in glial cell activation and the role of cytokines-associated RedoxEVs in the fate of neurons. Aim 2 will determine the efficacy of RAAs in preventing HGG and HGG treatment-associated CI in neurons and preclinical models. This aim will substantiate our RedoxEV hypothesis using the MnSOD mimetic, BMX-001, which has been shown in clinical trials to be safe and also to extend the survival of HGG patients. This study uses state-of-the-art platforms at the Center for Cancer and Metabolism (CCM) including stable isotope-resolved metabolomics, reverse phase protein arrays, and a super resolution resonance scanner confocal microscopy. The expertise of the team, CCM’s unique resources, and our seminal studies provide an ideal experimental context to study the impact of RedoxEVs in terms of mechanistic and proof-of-concept studies associated with CI. The data obtained from this project will provide a strong rationale for R01 application (tentatively 2025-2026) to investigate underlying mechanisms of how cancer and cancer treatments contribute to CI and offer a translational impact that can provide quality of life care to cancer patients suffering from CI.